Summary The endogenous cannabinoid system plays an important role in regulating the immune system. Modulation of endogenous cannabinoids represents an attractive alternative for the treatment of inflammatory disorders. This study investigated the effects of URB597, a selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme catalysing degradation of the endogenous cannabinoid anandamide, and AM404, an inhibitor of anandamide transport, on lipopolysaccharide (LPS)‐induced increases in plasma cytokine levels in rats. Both URB597 and AM404 potentiated the LPS‐induced increase in plasma tumour necrosis factor‐α (TNF‐α) levels. The peroxisome proliferator‐activated receptor γ (PPARγ) antagonist, GW9662, attenuated the AM404‐induced augmentation of TNF‐α levels. Furthermore, the selective cannabinoid CB1 and CB2 receptor antagonists, AM251 and AM630 respectively, and the transient receptor potential vanilloid receptor‐1 (TRPV1) antagonist, SB366791, reduced LPS‐induced TNF‐α plasma levels both alone and in combination with AM404. In contrast, AM404 inhibited LPS‐induced increases in circulating interleukin‐1β (IL‐1β) and IL‐6. AM251 attenuated the immunosuppressive effect of AM404 on IL‐1β. None of the antagonists altered the effect of AM404 on LPS‐induced IL‐6. Moreover, AM251, AM630 and SB366791, administered alone, inhibited LPS‐induced increases in plasma IL‐1β and IL‐6 levels. In conclusion, inhibition of endocannabinoid degradation or transport in vivo potentiates LPS‐induced increases in circulating TNF‐α levels, an effect which may be mediated by PPARγ and is also reduced by pharmacological blockade of CB1, CB2 and TRPV1. The immunosuppressive effect of AM404 on IL‐1β levels is mediated by the cannabinoid CB1 receptor. Improved understanding of endocannabinoid‐mediated regulation of immune function has fundamental physiological and potential therapeutic significance.

The mechanism of fat embolism following injury has excited much controversy since it was first described by Zenker in 1862. Two theories seek to explain it-the classical mechanical theory, which is supported by Sevitt (1962), and the metabolic theory, which is supported by Evarts (1965) In this study, firstly, an attempt was made to try to establish whether there was any change in the serum non-cholesterol lipids after trauma; secondly, the incidence of all degrees of the syndrome of fat embolism was investigated; and, thirdly, the effect of Atromid (clofibrate) on the serum lipids and the incidence of fat embolism was studied. Clofibrate was used because it has an effect on the lipids of the hyperlipaemic patient and has also been found to depress postprandial lipaemia. Material and MethodsThe patients were inmates of the orthopaedic unit at St. James's Hospital, Leeds, either as a result of injury serious enough to warrant admission or because they were undergoing orthopaedic surgery. They were divided into two groups (Table I). One group received standard therapy, and the other received clofibrate as well, as soon as they were able to take capsules. The dosage of clofibrate used was 750 mg. by mouth followed by 500 mg. six-hourly for two days, then 250 mg. six-hourly for three days, then 250 mg. twice daily for two days, and finally 250 mg. daily for two days. The dose was tailed off to prevent any rebound effects. Eight patients who had had operations on non-bony structures also received clofibrate. Laboratory EstimationsPlasma total lipids were estimated by the rapid turbimetric method of Kunkel et al. (1948), giving normal ranges between 340 and 640 mg./l00 ml. and a 5% error against standard sera. Cholesterol levels were measured by the method of Carr and Drekter (1956) on the first 30 samples and subsequently by direct estimation on an autoanalyser (Kenny and Jamieson, 1963). Cholesterol levels were then subtracted from the total levels to give the non-cholesterol lipid levels.Sputum was examined for fat globules by adding scharlach R and then by direct microscopy. Urine (end samples) were examined by centrifugation for five minutes, adding scharlach R to the deposit, and then by direct microscopy.

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